Using a PCR-based strategy, we found that point mutation frequencies in mitochondrial DNA (mtDNA)were 2- to 3-fold higher in the parietal gyrus, hippocampus, and cerebellum from subjects with Alzheimer's disease (AD) compared to normal controls. In contrast, levels of a commonly studied deletion mutation, mtDNA(4977), were not elevated in AD. The frequency of point mutations did not vary significantly among the three brain areas, whereas the frequency of mtDNA(4977) was 15- to 25-fold lower in the cerebellum in comparison to the cortex; this regional variation was seen in both the normal and Alzheimer's brain. In blood mtDNA, point mutation frequencies were not elevated in AD patients. The elevated frequency of point mutations in all three brain regions is consistent with the idea that increased oxidant stress is associated with AD,